The present invention relates to lobeline analogs, specifically cis-2,6-disubstituted piperidines, and their method of use in the treatment of diseases and pathologies of the central nervous system (CNS), the treatment of drug abuse and withdrawal therefrom as well as to the treatment of eating disorders such as obesity.
Alpha-Lobeline (lobeline), a lipophilic nonpyridino, alkaloidal constituent of Indian tobacco, is a major alkaloid in a family of structurally-related compounds found in Lobelia inflata. Lobeline has been reported to have many nicotine like effects, including tachycardia and hypertension (Olin et al., 1995), hyperalgesia (Hamann et al., 1994) and improvement of learning and memory (Decker et al., 1993). Lobeline has high affinity for nicotinic receptors (Lippiello et al., 1986; Broussolle et al., 1989). However, no obvious structural resemblance of lobeline to nicotine is apparent and structure function relationships between S(-)-nicotine and lobeline do not suggest a common pharmacophore (Barlow et al., 1989). Also, differential effects of lobeline and nicotine suggest that these drugs may not be active through a common CNS mechanism, even though lobeline has been considered a mixed nicotinic agonist/antagonist.
Lobeline evokes dopamine (DA) release from rat striatal slices. However, lobeline evoked DA release is neither dependent upon extracellular calcium nor is it sensitive to mecamylamine, a noncompetitive nicotinic receptor antagonist. Thus, lobeline evoked DA release occurs via a different mechanism than does nicotine to evoke DA release (Teng et al., 1997, 1998; Clarke et al., 1996). In this respect, lobeline also inhibits DA uptake into rat striatal synaptic vesicles via an interaction with the dihydrotetrabenazine (DTBZ) site on vesicular monoamine transporter-2 (VMAT2), thus increasing the cytosolic DA available for reverse transport by the plasma membrane transporter (DAT) (Teng et al., 1997, 1998). Thus, lobeline interacts with nicotinic receptors and blocks nicotine-evoked DA release, but also interacts with DA transporter proteins to modify the concentration of DA in the cytosolic and vesicular storage pools, thereby altering subsequent dopaminergic neurotransmission.
The present invention is directed to a method of treating an individual who suffers from a disease or pathology of the central nervous system (CNS) or for treating an individual for drug dependence or withdrawal for drug dependence. The method comprises of administering to the individual an effective amount of a cis-2,6-substituted piperidino compound, i.e., a lobeline analog, including pharmaceutically acceptable salts of such compounds thereof. As used herein, an xe2x80x9ceffective amountxe2x80x9d refers to an amount of a drug effective to reduce an individual""s desire for a drug of abuse or for food, or for alleviating at least one of the symptoms of the disease or pathological symptom of a CNS pathology.
The compound can be administered alone, combined with an excipient, co-administered with a second drug having a similar or synergistic effect. The compound is administered subcutaneously, intramuscularly, intravenously, transdermally, orally, intranasally, intrapulmonary or rectally. The use of cis-2,6-disubstituted piperidines and derivatives thereof in treating diseases or pathologies of the CNS is implicated. In particular, the treatment of dependencies of such drugs as cocaine, amphetamine, caffeine, nicotine, phencyclidine, opiates, barbiturates, benzodiazepines, canabinoids, hallucinogens, and alcohol is implicated. Also, the treatment of eating disorders such as obesity is implicated.
In a preferred aspect of the invention, the method of treatment reduces an individual""s desire for the drug of abuse or for food by at least one day, but it is also preferred that the treatment method further comprise administering behavior modification counseling to the individual. Although the compound of the present invention is contemplated primarily for the treatment of drug abuse and withdrawal and for eating disorders, other uses are also suggested by the studies discussed herein. Thus, cognitive disorders, brain trauma, memory loss, psychosis, sleep disorders, obsessive compulsive disorders, panic disorders, myasthenia gravis, Parkinson""s disease, Alzheimer""s disease, schizophrenia, Tourette""s syndrome, Huntington""s disease, attention deficit disorder, hyperkinetic syndrome, chronic nervous exhaustion, narcolepsy, motion sickness and depression, and related conditions are considered to be susceptible to treatment with a compound of the present invention.
As shown by the results of the studies described herein, lobeline analogs are found to be effective in inhibiting uptake of extracellular DA by cells of the CNS. Some of these analogs are a also nicotinic receptor antagonists. Either or both mechanisms can thereby work to alter the distribution of the intracellular DA pools and as a result alter extracellular DA concentration.
As used herein the term xe2x80x9clobelinexe2x80x9d refers to a compound having the general chemical formula 2-[6-(xcex2-hydroxyphenethyl)-1-methyl-2-piperidyl]-acetophenone. The term xe2x80x9clobeline analogsxe2x80x9d and equivalents thereof as used herein, refers to chemical derivatives of lobeline obtained by oxidation or reduction of lobeline, others obtained by esterification of lobeline and redox derivatives, as well as various substitutions at the N-position of the piperidinyl moiety.
The 2,6-disubstituted piperidine lobeline analogs of the present invention include those contemplated by the following formula (I), without regard to chirality: 
wherein:
n is zero or an integer in the range from 1 to 3;
X1 - - - Y1 and X2 - - - Y2 are the same or are independently different from one another and represent a saturated carbon-carbon bond, a cis-carbon-carbon double bond, a trans-carbon-carbon double bond, a carbon-carbon triple bond; a saturated sulfur-carbon bond, a saturated selenium-carbon bond, an oxygen-carbon bond, a saturated nitrogen-carbon bond, a N-alkyl substituted saturated nitrogen-carbon bond where said alkyl is a lower straight chain or branched alkyl, a nitrogen-carbon double bond, or a nitrogen-nitrogen double bond;
R1 and R4 are the same or are independently different from one another and represent hydrogen or a lower straight chain or branched alkyl or R1 and R4 together form a ring including a xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94CH2xe2x80x94, xe2x80x94cisxe2x80x94CHxe2x95x90CH, xe2x80x94cisxe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94or xe2x80x94cisxe2x80x94CH2xe2x95x90CHxe2x80x94CH2xe2x80x94 moiety;
R2 and R3 are the same or are independently different from one another and represent a saturated or unsaturated hydrocarbon ring; a nitrogen containing heterocyclic moiety; an oxygen containing heterocyclic moiety; a sulfur containing heterocyclic moiety; a selenium containing heterocyclic moiety; a mixed heterocyclic moiety containing at least two atoms selected from the group consisting of nitrogen, oxygen and sulfur; and an ortho, meta or para-substituted benzene;
with the proviso that when n=0, R2 and R3 are unsubstituted phenyl groups, and X1 - - - Y1 and X2 - - - Y2 are saturated carbon-carbon bonds, Y1 cannot be CH2, CHOH or Cxe2x95x90O, and Y2 cannot be CH2, CHOH, or Cxe2x95x90O.
It is preferred that when R3 and/or R4 is a saturated hydrocarbon ring, the ring includes, but is not limited to, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.
It is further preferred that when R3 and/or R4 is an unsaturated hydrocarbon ring, the ring includes, but is not limited to, benzene, cyclopentene, cyclohexene, cycloheptene, cyclooctene or cyclopentadiene, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.
It is further preferred that when R3 and/or R4 is a nitrogen containing heterocyclic moiety, the moiety includes, but is not limited to, azetine, piperdine, piperazine, pyrazine, pyrazole, pyrazolidine, imidazole imidazoline, pyrimidine, hexa-hydropyrimidine, pyrrole, pyrrolidine, triazine, 1,2,3-triazole, 1,2,4-triazole, pyridine or pyridazine, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.
It is further preferred that R3 and/or R4 is an oxygen containing heterocyclic moiety, the moiety includes, but is not limited to, furan, tetrahydrofuran, 2,5-dihydrofuran, pyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane or 1,4-oxathinin, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and, enantiomeric forms thereof.
It is further preferred that when R3 and/or R4 is a sulfur containing heterocyclic moiety, the moiety includes, but is not limited to, thietane, thiophene, thiophane, 2,5-dihydrothiophene, 1,3-dithiolylium, 1,3-dithiolane, 1,2-dithiolylium, 1,2-dithiolane, thiane, 1,2-dithiane, 1,3-dithane, 1,4-dithiane, or thiopyranylium, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.
It is further preferred that when R3 and/or R4 is a selenium containing heterocyclic moiety, the moiety includes, but is not limited to, selenophene, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.
It is further preferred that when R3 and/or R4 is a mixed heterocyclic moiety, the moiety includes, but is not limited to, thiazolidine, thiazole and oxazin, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.
The substituted benzene includes at least one substituent, where the substituent is selected from , but is not limited to, the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, amino, N-methylamino, N,N-dimethylamino, carboxylate, methylcarboxylate, ethylcarboxylate, propylcarboxylate, isopropylcarboxylate, carboxaldehyde, acetoxy, propionyloxy, isopropionyloxy, cyano, aminomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, acetyl, propionyl, formyl, benzoyl, sulfate, methylsulfate, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, thiol, methylthio, ethylthio, propiothiol, fluoro, chloro, bromo, iodo, trifluoromethyl, vinyl, allyl, propargyl, nitro, carbamoyl, ureido, azido, isocyanate, thioisocyanate, hydroxylamino and nitroso.
It is preferred that when either X1 - - - Y1 or X2 - - - Y2 is a saturated carbon-carbon bond, Y1 or Y2 represents CH2, CHxe2x80x94OH, CHO-alkyl where said alkyl is a lower straight chain or branched alkyl, CHxe2x80x94OSO2xe2x80x94C6H5, CHxe2x80x94OSO2-p-C6H4CH3, CHxe2x80x94SH, C6H5xe2x80x94SH, CHxe2x80x94S-alkyl where said alkyl is a lower straight chain or branched alkyl, CHxe2x80x94NO2, CHxe2x80x94CF3, CHxe2x80x94NHOH, CHxe2x80x94OCHO, CHxe2x80x94F, CHxe2x80x94Cl, CHxe2x80x94Br, CHxe2x80x94I, CHxe2x80x94NH2, CHxe2x80x94NH-alkyl where said alkyl is a lower straight chain or branched alkyl, CHxe2x80x94N(alkyl)2 where said alkyl is a lower straight chain or branched alkyl, CHxe2x80x94OCONH2, CHxe2x80x94OCONH-alkyl where said alkyl is a lower straight chain or branched alkyl, CHxe2x80x94OCON(alkyl)2 where said alkyl is a lower straight chain or branched alkyl, CHxe2x80x94N3, Cxe2x95x90O or Cxe2x95x90S; CHxe2x80x94O-aryl such as a phenyl, ortho-, meta-, or para-substituted phenyl where the substituent is as described above; or a hydrocarbon or hetercyclic ring such as pyridyl, furanyl, naphthyl, thiazole, selenothenyl, oxazolyl, 1,2,3-triazole, 1,2,4-triazole, imidazoline, pyrimidine, pyridazine or triazine, including all possible substitution patterns, diastereomeric and enantiomeric forms thereof.
The lower straight or branched alkyl can be an alkyl group containing one to seven carbon atoms. The preferred alkyl groups are methyl and ethyl.
The above 2,6-substituted piperidino analogs are preferred in their cis-geometrical isomeric forms, or in their trans geometric forms, including all possible geometric, racemic, diasteriomeric, and enantiomeric forms thereof.
The above cis-2,6-disubstituted piperidines as well as analogs thereof can be administered in their free base form or as a soluble salt. Whenever it is desired to employ a salt of a cis-2,6-substituted piperidine or its analog, it is preferred that a soluble salt be employed. Some preferred salts include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, tartrate, galactarate, fumarate, citrate, maleate, glycolate, malate, ascorbate, lactate, aspartate, glutamate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, salicylate, proprionate, and succinate salts. The above salt forms may be in some cases hydrates or solvates with alcohols and other solvents.
A pharmaceutical composition containing a compound of the invention is also contemplated, which may include a conventional additive, such as a stabilizer, buffer, salt, preservative, filler, flavor enhancer and the like, as known to those skilled in the art. Representative buffers include phosphates, carbonates, citrates and the like. Exemplary preservatives include EDTA, EGTA, BHA, BHT and the like. A composition of the invention may be administered by inhalation, i.e., intranasally as an aerosol or nasal formulation; topically, i.e., in the form of an ointment, cream or lotion; orally, i.e., in solid or liquid form (tablet, gel cap, time release capsule, powder, solution, or suspension in aqueous or non aqueous liquid; intravenously as an infusion or injection, i.e., as a solution, suspension or emulsion in a pharmaceutically acceptable carrier; transdermally, e.g., via a transdermal patch; rectally as a suppository and the like.
Generally, the pharmacologically effective dose of a present compound is in the amount ranging from about 1xc3x9710xe2x88x925 to about 1 mg/kg body weight/day. The amount to be administered depends to some extent on the lipophilicity of the specific compound selected, since it is expected that this property of the compound will cause it to partition into fat deposits of the subject. The precise amount to be administered can be determined by the skilled practitioner in view of desired dosages, side effects and medical history of the patient and the like.
The cis-2,6-disubstituted piperidino analogs of the present invention exhibit selectivity for either neuronal nicotinic acetylcholine receptors and/or the dopamine transporter protein (DAT). The derivatives that are active towards the nicotinic receptor generally do not interact with the DAT, and those that interact with the DAT show only modest nicotinic receptor activity.
The nine cis-2,6-disubstituted piperidino derivatives listed in Table 1 have the chemical structure of formula (II). They were assayed for nicotinic receptor interaction and inhibition of DAT activity. The cis-2,6-disubstituted piperidino analogs of the present invention exhibit selectivity for either neuronal nicotinic acetylcholine receptors and/or the dopamine transporter protein (DAT). The derivatives that are active towards the nicotinic receptor generally do not interact with the DAT, and those that interact with the DAT show only modest nicotinic receptor activity.
The nine compounds in Table 1 were evaluated in the high affinity [3H]nicotine binding assay and afforded inhibition constants (Ki values) ranging from 0.0043 xcexcM to  greater than 100 xcexcM. Five of these compounds were in the range of 4-160 nM. Three of these compounds were in the range of 0.93-14 FM. One compound was  greater than 100 RM. The cis-2,6-disubstituted piperidino derivatives listed in Table 1 were also assayed for inhibition of DAT activity, i.e., inhibition of [3H]DA uptake into the dopaminergic presynaptic terminal. Nine compounds were evaluated and afforded inhibition constants (Ki values) ranging from 0.08 xcexcM to 54 xcexcM.
Removal of both functionalities of the lobeline molecule resulted in loss of affinity for the nicotinic receptor and a 100-fold more potent inhibition of the dopamine transporter compared with lobeline. Removal of either the hydroxyl group or the keto group of lobeline resulted in a 50-fold loss of affinity for the nicotinic receptor. Interestingly, the ketoalkene analog inhibited DAT 10-fold more potently than lobeline, whereas lobelanidine inhibited DAT equipotently compared to lobeline. Conversion of the hydroxy group of lobeline to a bulky tosyloxy group reduced the affinity of the nicotinic receptor by only 3-fold, but did not alter the interaction with the DA transporter. The hydroxyalkene had a similar potency with the meso-transdiene (the most potent compound) in the DA uptake assay, but had 1000-fold lower affinity for the nicotinic receptor. Also, the completely defunctionalized lobeline molecule and the hydroxyalkane analog were both less potent than the meso-transdiene in inhibiting DA uptake into striatal synaptosomes. This data indicates that appropriate structural modification of the lobeline molecule affords compounds in which the interaction with DAT is enhanced. Furthermore, in one compound, i.e., the meso-transdiene, the nicotinic receptor interaction has been eliminated and the compound is thus selective for inhibition of DAT.